Platinum-diamine complexes, a method for the preparation of a medicine using such a platinum-diamine complex for the treatment of malignant tumor in mice

ABSTRACT

This invention relates to novel platinum-diamine complexes having the formula: ##STR1## wherein R 1  and R 2  independently of each other may be selected from the group consisting of hydrogen, an alkyl group having 1-20 carbon atoms, a cycloalkyl group having from 3-7 carbon atoms in the ring, an aralkyl group, and an aryl group having 1-20 carbon atoms, whereas R 1  and R 2  together may form a cycloalkyl group having 3-7 carbon atoms in the ring and having the formula: ##STR2## wherein N is 2 to 7 and wherein R 3  and R 4  independently of each other are selected from the group consisting of hydrogen, an alkyl group having 1-20 carbon atoms, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group and X is an anionic group, providing that when X is either chlorine or malonate, R 1 , R 2 , R 3  and R 4  are not each H; when X is chlorine and R 1  and R 2  are each H, R 3  and R 4  are not each methyl; when X is chlorine and R 1  and R 2  are each methyl, R 3  and R 4  are not each H, and when X is chlorine R 1  is hydrogen and R 2  is methyl and R 3  and R 4  are not each hydrogen.

This application is a continuation-in-part of application Ser. No.054,891 filed July 5, 1979 now abandoned.

The invention relates to novel platinum-diamine complexes, and to apharmaceutical composition using such a platinum-diamine complex for thetreatment of mice, for example, malignant swellings and malignant tumorsin mammals.

Platinum-diamine complexes are known from the article by A. P. Zipp andS. G. Zipp, J. Chem. Ed., 54 (12) (1977), page 739, which describes theapplication of cis-platinum diamine dichloride (PDD) for the treatmentof cancer. It is known that platinum compounds have a broad spectrum ofactivity as antitumor agents, but also that they have serious drawbacks,in particular that they are toxic to the kidneys. Cis-platinum diaminedichloride is often used in combination with another substance oradministered with large quantities of liquid or other techniques areused to bring about an adequate flow-through of the kidneys, as a methodfor counteracting kidney toxicity. A number of other platinum aminecomplexes are known including compounds having the formula: ##STR3##

Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-134, discloses a largenumber of platinum diamine complexes, including cis platinum diaminedichloride, for the treatment of cancer. Here, too, the kidney toxicityis stated as the most important drawback of these compounds.

Chem. and Eng. News, 6th June 1977, pp. 29-30, also describescis-platinum diamine dichloride and its application for the treatment ofcancer. Kidney toxicity is also mentioned as the most important drawbackof these compounds.

In an article in Cancer Chemotherapy Reports Part 1, Vol. 59, No. 3,May/June 1975, pp. 629-641. The kidney toxicity of cis-platinum diaminedichloride is also reported. Because of the toxicity of PDD to thekidney and its low therapeutic index, other platinum complexes for thetreatment of cancer have been sought. For this purpose combinations ofcis-platinum diamine dichloride with other chemotherapeutic agents weretested. Novel platinum complexes were also tried, but they were alsofound to be too toxic. It was found, for instance, that althoughcis-dichlorobiscyclopentyl amine platinum(II) is only slightly toxic tothe kidneys, it is toxic to the spleen. So-called "platinum blues", amixture of different amounts of five or more inseparable components havealso been disclosed for the treatment of cancer.

Dutch Patent Applications Nos. 73,04880; 73,04881; 73,04882 and 77,03752disclose a large number of platinum diamine complexes, including thecompound having formula (5) above. In all of these compounds with anucleus, nitrogen atoms are linked directly to the nucleus. Thecompounds of the first three Dutch applications were compared withcis-platinum diamine dichloride and were found to have better effects.None of the patent applications states anything about toxicity.

Toxicity is a very serious drawback of PDD, as well as all otheranti-cancerous platinum complexes that have been used so far. The hightoxicity of these compounds, especially the kidney toxicity which is themost dangerous one, actually limits the dose of the drug that can begiven to a subject.

In spite of the considerable research in this field prior to thisinvention, no one has succeeded in developing compounds withanti-cancerous activity comparable to that of PDD, but withsignificantly lower toxicity, especially kidney toxicity.

Novel platinum diamine complexes have now been found that are suitablefor the treatment of mice in mammals and that display little or nokidney toxicity.

The platinum diamine complexes according to the invention arecharacterized by the formula: ##STR4## wherein R₁ and R₂ independentlyof each other may be selected from the group consisting of hydrogen, analkyl group having 1-20 carbon atoms, a cycloalkyl group having from 3-7carbon atoms in the ring, an aralkyl group, and an aryl group, whereasR₁ and R₂ together may form a cycloalkyl group having 3-7 carbon atomsin the ring and having the formula: ##STR5## wherein n is 2 to 7 andwherein R₃ and R₄ independently of each other are selected from thegroup consisting of hydrogen, an alkyl group having 1-20 carbon atoms,an aryl group or an aralkyl group having 1-20 carbon atoms in the alkylgroup and X is an anionic group, providing that when X is eitherchlorine or malonato, R₁, R₂, R₃ and R₄ are not each H; when X ischlorine and R₁ and R₂ are each H, R₃ and R₄ are not each methyl; when Xis chlorine and R₁ and R₂ are each methyl, R₃ and R₄ are not each H, andwhen X is chlorine R₁ is hydrogen and R₂ is methyl and R₃ and R₄ are noteach hydrogen.

Compounds having the following formula: ##STR6## in which R₃, R₄ and Xhas the same meaning as in formula 1 are preferred, for example,cis-dichloro-1, 1-di(aminomethyl)cycloalkyl platinum(II), having theformula: ##STR7## wherein n is 2-7, preferably 3-5 and cis-dichloro-1,1-di(aminomethyl)cyclohexyl platinum(II) having the following formula:##STR8##

In formulas 1-2 the anionic group X preferably is a chlorine, bromine oriodine, sulphate, phthalate, acetate, carboxylate, an oxalate, malonateor substituted malonate group and isocitrate. The acetate can be, forexample, chloroacetate. The substituents on a malonate group could be,for example, hydroxy or ethyl.

The invention further relates to a pharmaceutical composition in whichthese novel compounds are used as the active ingredient. In preparingthe pharmaceutical compositions, the novel compounds are mixed withknown liquid or solid carriers to form injectable liquids or oralpreparations.

An extensive research program carried out by the National CancerInstitute, Bethesda, Md., and the European Organization for Research onthe Treatment of Cancer, Brussels, Belgium, has shown that when comparedto PDD, compounds according to this invention, particularly compoundshaving the following formulas display a high therapeutic activityagainst a great number of different mammalian types of tumor, such as P388 lymphocytic leukemia (PS), L-1210 lymphoid leukemia (LE),ependymoblastoma (EM), B 16 melanocarcinoma (B₁) and a line of L-1210leukemia resistant to cis-PDD (LE/cis-PDD): ##STR9##

The results of these experiments are set forth in Table A. It isimportant to note that compounds, such as those having formulas 17, 18or 19 appeared to be even more effective against the cis-PDD resistantline of L-1210 than they are against the parent line of L-1210. Inseveral cases complete cures were observed with the novel compounds, aneffect which was not observed with cis-PDD.

More detailed information concerning the testing procedure and theirinterpretation are contained in Instruction 14, Screening Data Summary,Interpretation and Outline of Current Screen, Drug Evaluation Branch,National Cancer Institute, Bethesda, Md., 20014 (1977) which isincorporated herein by reference.

                  TABLE A.                                                        ______________________________________                                        Anti-cancerous activity in mice                                                                            Dose/                                                     Mouse               injection                                                                            T/C*                                      Compound Code     Tumor      (mg/kg)                                                                              (%)                                       ______________________________________                                        Formula 4                                                                              CD.sub.2 F.sub.1                                                                       PS          6.25  201                                                                     3.12  181                                                                     1.56  153                                       Formula 4                                                                              CD.sub.2 F.sub.1                                                                       LE         12.50  234                                                                     6.25  180                                                                     3.12  145                                       Formula 4                                                                              C57BL/6  EM          6.00  126                                       Formula 4                                                                              B.sub.6 D.sub.2                                                                        Bl          6.00  208                                                (BDF)                3.00  208                                                                     1.50  190                                       PDD      B.sub.6 D.sub.2                                                                        Bl          2.00  197                                                (BDF)                                                                Formula 7                                                                              CD.sub.2 F.sub.1                                                                       PS         25.00  226                                                                    12.50  177                                                                     6.25  162                                       Formula 7                                                                              CD.sub.2 F.sub.1                                                                       LE         80.00  138                                       Formula 7                                                                              57BL/6   EM         12.50  163                                                                     6.25  130                                       Formula 8                                                                              CD.sub.2 F.sub.1                                                                       LE         12.50  289                                       Formula 9                                                                              CD.sub.2 F.sub.1                                                                       LE         12.50  323                                       Formula 11                                                                             CD.sub.2 F.sub.1                                                                       LE         12.50  274                                       Formula 10                                                                             CD.sub.2 F.sub.1                                                                       LE         12.50  148                                       Formula 12**                                                                           BDF.sub.1                                                                              LE         15.00  208                                       Formula 13                                                                             BDF.sub.1                                                                              LE         50.00  135                                       Formula 14                                                                             BDF.sub.1                                                                              LE         50.00  178                                       Formula 15                                                                             BDF.sub.1                                                                              LE         40.00  200                                       Formula 16                                                                             BDF.sub.1                                                                              LE          6.00  207                                       Formula 17                                                                             BDF.sub.1                                                                              LE         12.00  200                                       Formula 17                                                                             BDF.sub.1                                                                              LE/cis PDD  6.00  >500 (3/6)                                Formula 18                                                                             BDF.sub.1                                                                              LE         64.00   200 (1/6)                                Formula 18                                                                             BDF.sub.1                                                                              LE/cis PDD 16.00  230                                       Formula 19                                                                             BDF.sub.1                                                                              LE         36.00  246                                       Formula 19                                                                             BDF.sub.1                                                                              LE/cis PDD 24.00  >500 (3/6)                                Cis PDD  BDF.sub.1                                                                              LE          8.00  183                                       Cis PDD  BDF.sub.1                                                                              LE/cis PDD 4-8    106-121                                   ______________________________________                                         *Period of survival is the ratio of survival times of the treated mice (T     to untreated mice (C); the therapeutic activity is significant at T/C         ≧ 125. The figures include dying mice only. A cure is defined as a     mouse free of tumors 45 days after injection, as determined by visual         inspection at autopsy.                                                        **For Formula 12-cis PDD the mice were injected with 10.sup.6 L1210           ascites cells. One I.P. injection of the test compound was given to each      of six mice.                                                             

                  TABLE B.                                                        ______________________________________                                        Percentage of urea-nitrogen in the blood after                                administering platinum complexes (in the rat).                                                      Number of Percentage of                                            Dose       days after                                                                              urea-nitrogen                                 Compound   (mg/kg)    injection in blood                                      ______________________________________                                        Formula 4  8(LD.sub.10)                                                                             0         10                                                                  2         10                                                                  4         15                                            Formula 4  15(LD.sub.50)                                                                            0         10                                                                  2         15                                                                  4         17                                            Controls     --       0         10                                                                  2          9                                                                  4         11                                            √PDD                                                                              3(LD.sub.10)                                                                             0         10                                                                  2         13                                                                  4         52                                                       7.6(LD.sub.50)                                                                           0         10                                                                  2         78                                                                  4         148                                           ______________________________________                                    

Blood urea nitrogen (BUN) levels were also evaluated for the micetreated with compounds having formulas 12-19 on 4, 7 and 11 days afterdrug administration. In comparison with rats treated with cis-PDD, noneof the compounds having formulas 12-19 caused a significant elevation ofthe BUN values.

The data in Table B demonstrate that compounds according to thisinvention do not have any effect on the urea-nitrogen content in theblood (BUN). Both at doses corresponding with the LD₁₀ -amount and atthose corresponding with the LD₅₀ -amount the urea-nitrogen contents inthe blood are identical to the control values. BUN values≧30 mg% aregenerally considered indicative of drug-induced nephrotoxicity. Incontrast, PDD at a LD₁₀ -dose, 4 days after injection, caused about aquadruple increase in the urea nitrogen content. In was found by meansof a histological examination of rats after treatment with toxic dosesof compounds of this invention, that these compounds display little orno kidney toxicity.

The preparation of the compounds listed in Tables A and B are shown inthe following examples.

The compounds were prepared according to the method by S. C. Dhara;Indian J. Chem. 8, 193 (1970).

EXAMPLE 1 Cis-diiodo-1,1-di(aminomethyl)cyclohexane platinum(II) (6)having the formula: ##STR10##

To a solution of 16 g K₂ PtCl₄ in 160 ml of water a solution of 26.4 gKI in 20 ml of water were added and the mixture was heated for 5 min. ina water bath.

Hereupon 6.4 g 1,1-di(aminomethyl)cyclohexane were added and after themixture had been stirred for 5 minutes, the precipitate was sucked andwashed three times with hot water, twice with cold ethyl alcohol andtwice with ether.

Yield 22.1 g.

EXAMPLE 2 Cis-dichloro-1,1-di(aminomethyl)cyclohexane platinum(II) (4)

11.8 g of the diiodo derivative, prepared according to Example 1, wereadded to a solution of 6.6 g AgNO₃ in 48 ml water.

After the mixture had been stirred for 10 minutes at 95°-100° C., theAgI was filtered off and washed with water. To the clear filtrate 3.28 gKCl were added and the mixture was stirred for 12 min. at 95°-100° C.After the mixture had been cooled, the precipitate was sucked and washedwith water.

Yield: 6.0 g.

Analysis (percentage by weight): Calcul.: C: 23.53; H: 4.45; N: 6.87;Pt: 47.80; Found: C: 23.32; H: 4.46; N: 6.86; Pt: 47.63.

EXAMPLE 3 Cis-cyclopentamethylenemalonato-1,1-di(aminomethyl)cyclohexane platinum(II) (7)

20.65 g the diiode derivative, prepared according to Example 1, wereadded to a solution of 11.55 g AgNO₃ in 85 ml of water.

After the solution had been stirred for 10 minutes at 95°-100° C., theAgI was filtered off and washed with water. When the filtrate was stillhot, a solution of 5.0323 g cyclopentamethylene malonic acid in 114.34ml 0.51125 N NaOH were added and the mixture was heated for 12 min. at95°-100° C. After the mixture had been cooled, the precipitate wassucked and washed with water. After drying under reduced pressure theproduct obtained was extracted with 4 l methanol, the methanol solutionwas treated with activated carbon, filtered until it was clear and thefiltrate evaporated to dryness under reduced pressure. The residue wassuspended in 500 ml alcohol, sucked off and washed with methanol.

Yield 4.75 g.

Analysis (percentage by weight): Calcul.: C: 37.86; H: 5.56; N: 5.52;Pt: 38.46. Found: C: 37.50; H: 5.50; N: 5.60; Pt: 38.19.

Analogous to Examples 1 and 2, the following compounds were prepared,which are very pale yellow crystalline substances.

EXAMPLE 4 Cis-dichloro-(2-methyl-2-ethyl)-1,3-propane diamine platinum(II) (8) having the formula ##STR11##

Yield: 55% by weight.

Analysis (% by weight): Calcul.: C: 18.86; H: 4.22; N: 7.33; Pt: 51.04;Cl: 18.55. C: 18.73; H: 4.14; N: 7.26; Pt: 51.33; Cl: 18.69.

EXAMPLE 5 Cis-dichloro-2,2-diethyl-1,3-propane diamine platinum(II) (9)having the formula: ##STR12##

Yield: 70% by weight.

Analysis (% by weight): Calcul.: C: 21.22; H: 4.58; N: 7.07; Pt: 49.24;Cl: 17.89. C: 21.04; H: 4.50; N: 7.02; Pt: 49.43; Cl: 17.83.

EXAMPLE 6 Cis-dichloro-1,1-di(aminomethyl)cyclopentane platinum(II) (10)having the formula: ##STR13##

Yield: 70% by weight.

Analysis (% by weight): Calcul.: C: 21.33; H: 4.09; N: 7.11; Pt: 49.49;Cl: 17.98; Found: C: 21.36; H: 4.10; N: 7.14; Pt: 49.27; Cl: 17.91.

EXAMPLE 7 Cis-1,1-di(aminomethyl)cyclohexane platinum(II) sulphate (11)having the formula: ##STR14##

2 g diiodo derivative, prepared as in Example 1, were suspended in 150ml water. After stirring during 20 hours with 1.0 g Ag₂ SO₄ the AgI wasfiltered off and washed with H₂ O. The clear filtrate was evaporated.

Yield: 1.1 g˜80% by weight.

Analysis (% by weight): Calcul.: C: 22.17; H: 4.19; N: 6.46; Found: C:22.02; H: 4.62; N: 6.31.

The following compounds in Examples 8 to 10 were prepared according tothe Method of G. L. Johnson: Inorg. Synth. VIII, pp. 242-244.

EXAMPLE 8 Cis-dichloro-1,1-di(aminomethyl)cyclobutane platinum(II) (12)having the formula: ##STR15##

2.8 g 1,1-di(aminomethyl)-cyclobutane, 2 g HCl and 6.2 g K₂ PtCl₄ weredissolved in 50 ml water, heated to 95°-100° C. and to this 1.2 g NaOHin 25 ml water were dropwise added so quickly that the pH was maintainedat ±6.

The precipitate formed was sucked, washed with water and dried. Theproduct was taken up in 250-300 ml aqueous NH₃ and filtered. Afterevaporating NH₃ the product was washed with 2 N HCl, water and dried.

Yield: 3.7 g˜65% by weight.

Analysis (% by weight): Calcul.: C: 18.96; H: 3.71; N: 7.37; Pt:51.31;Cl: 18.65; Found: C: 18.95; H: 3.67; N: 7.37; Pt: 51.02; Cl: 18.47.

EXAMPLE 9 Cis-dichloro-2,2-dibenzyl-1,3-propane diamine platinum(II)(13) ##STR16##

Yield: 45% by weight.

Analysis: (% by weight): Calcul.: C: 39.24; H: 4.26; N: 5.38; Found: C:39.81; H: 4.38; N: 5.73.

EXAMPLE 10 Cis-dichloro-2,2-diisopropyl-1,3-propane diamine platinum(II)(14) ##STR17##

Prepared as in Example 9.

Analysis (% by weight):

Calcul.: C: 25.48; H: 5.23, N: 6.60. Found: C: 26.31; H: 5.39; N: 6.90.

EXAMPLE 11 Cis-4-carboxyphthalato-1,1-di(aminomethyl)-cyclohexaneplatinum (II) having formula 15

1.2 g of the dichloro derivative prepared according to Example 2(formula 4), were added to a solution of 1 g AgNO₃ in 25 ml of water.

After the mixture has been stirred for 1 h. at 40° C. the AgCl wasfiltered off and washed with water.

To the clear filtrate 0.63 g of 1,2,4-tricarboxybenzene were added andthe mixture was stirred for 2 h. at room temperature. The precipitatewas sucked and washed with water.

Yield 0.8 g (45% by weight)

Analysis (% by weight): Calcul.: C: 36.24; H: 4.29; N: 4.97; Found: C:36.42; H: 4.13; N: 4.77.

EXAMPLE 12Cis-1,1-di(aminomethyl)-cyclohexane-bis(chloroacetato)platinum(II)having formula 16

1.6 g of the dichloro derivative prepared according to Example 2(formula 4), were added to a solution of 1.28 g AgNO₃ in 25 ml of water.

After stirring the mixture for 1 h. at 40° C. the AgCl was filtered offand washed with water.

To the clear filtrate a solution of 0.73 g of monochloroacetic acid and0.45 g KOH in 25 ml of water were added and the mixture was stirred for2 h. at room temperature. The precipitate was sucked and washed withwater.

Yield: 1.3 g (65% by weight).

Analysis (% by weight):

Calcul.: C: 27.49; H: 4.23; H: 5.34; Found: C: 27.43; H: 4.21; H: 5.55.

The following compounds were prepared as in Example 7.

EXAMPLE 13 Cis-2,2-diethyl-1,3-propanediamine platinum(II) sulphatehaving formula 17

Yield: 90% by weight.

Analysis (% by weight): Calcul.: C: 19.95; H: 4.27; N: 6.65; Found: C:20.06; H: 4.46; H: 6.68.

EXAMPLE 14 Cis-1,1-di(aminomethyl)-cyclohexanemalonato platinum(II)having formula 18

1.6 g of the dichloro derivative prepared according to Example 2(formula 4), were added to a solution of 1.28 g AgNO₃ in 25 ml of water.

After stirring the mixture for 1 h. at 40° C. the AgCl was filtered offand washed with water.

To the clear filtrate a solution of 0.4 g of malonic acid and 0.455 gKOH in 10 ml of water was added.

After stirring for 2 h. at room temperature the precipitate was filteredoff and dried.

Yield: 1.0 g (59% by weight).

Analysis (% by weight): Calcul.: C: 30.07; H: 4.59; H: 6.38; Pt: 44.40;O: 14.57; Found: C: 29.98; H: 4.54; H: 6.32; Pt: 44.32; O: 14.57.

EXAMPLE 15 Cis-1,1-di(aminomethyl)cyclohexanehydroxymalonatoplatinum(II) having formula 19 was prepared according to Example 14

Yield: 77% by weight.

Analysis (% by weight): Calcul.: C: 29.01; H: 4.43; N: 6.15; Pt: 42.84;O: 17.58; Found: C: 28.77; H: 4.38; N: 6.18; Pt: 42.96; O: 17.54.

Compounds having the following formulas not listed in Table A wereprepared according to Example 14: ##STR18##

EXAMPLE 16 Cis-2,2-diethyl-1,3-diaminopropane 2-ethylmalonatoplatinum(II) having formula 20.

Yield: 65% by weight.

Analysis (% by weight): Calcul. +2H₂ O: C: 29.33; H: 5.74; N: 5.70;Found: C: 29.23; H: 5.64; N: 5.71.

EXAMPLE 17 Cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonatoplatinum(II) having formula 21

Yield: 87% by weight.

Analysis (% by weight): Calcul. +1/2H₂ O: C: 26.55; H: 4.68; N: 6.19;Found: C: 26.67; H: 4.56; N: 6.23.

EXAMPLE 18 Cis-1,1-di(aminomethyl)cyclohexane 2-ethyl-malonatoplatinum(II) having formula 22

Yield: 64% by weight.

Analysis (% by weight): Calcul. +1,5H₂ O: C: 31.57; H: 5.50; N: 5.67;O:17.79; Pt: 39.43; Found: C: 31.36; H: 5.47; N: 5.69; O: 18.02; Pt:39.58.

EXAMPLE 19 Cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonatoplatinum(II) sodium salt having formula 23

0.5 g of the hydroxymalonato derivative prepared according to Example 17(formula 21) were suspended in 25 ml of water.

1.105 ml of 0.1 N NaOH were added and the mixture was stirred for 30min. at room temperature.

The clear solution was evaporated and the remaining solid dried.

Yield: 0.4 g (72% by weight).

Analysis (% by weight): Calcul. +2H₂ O: C: 23.91; H: 4.61; N: 5.58;Found: C: 23.75; H: 4.44; N: 5.52.

EXAMPLE 20 Cis-1,1-di(aminomethyl)cyclohexane1,1-cyclobutanedicarboxylato platinum(II) having formula 24.

2 g of the dichloro compound, prepared according to Example 2 (formula4) were added to a solution of 1.6 g AgNO₃ in 25 ml of water.

After stirring the mixture for 1 h. at 40° C. the AgCl was filtered offand washed with water.

To the clear filtrate a solution of 0.677 g of1,1-cyclobutanedicarboxylicacid and 0.547 g of KOH in 10 ml of water.

After 2 h. at room temperature and 1 h. at 0° C. the white precipitatewas filtered off and dried.

Yield: 1.4 g (62% by weight).

Analysis (% by weight): Calcul. +H₂ O: C: 33.80; H: 5.27; N: 5.63;Found: C: 33.98; H: 5.02; N: 5.77.

Compounds having the following formulas were prepared as in Example 20:##STR19##

EXAMPLE 21 Cis-2,2-diethyl-1,3-diaminopropane1,1-cyclobutanedicarboxylato platinum(II) having formula 25

Yield: 64% by weight.

Analysis (% by weight): Calcul. +2.5H₂ O: C: 30.46; H: 5.70; N: 5.47;Pt: 38.07; Found: C: 30.40; H: 5.44; N: 5.37; Pt: 38.16.

EXAMPLE 22 Cis-1,1-di(aminomethyl)cyclohexane platinum(II) isocitratehaving formula 26

4 g of the dichloro compound, prepared according to Example 2 (formula4) were added to a solution of 3.2 g AgNO₃ in 30 ml of water.

After stirring the mixture for 1 h. at 40° C. the AgCl was filtered offand washed with water.

To the clear filtrate a solution of 2.85 g of DL-isocitric aciddi-sodium salt in 15 ml of water were added and the mixture was stirredfor 2 h. at room temperature. The precipitate was sucked off and washedwith water.

Yield: 3.5 g (68% by weight).

Analysis (% by weight): Calcul: C: 31.88; H: 4.59; H: 5.31; Found: C:30.8; H: 4.9; H: 5.0.

We claim:
 1. Platinum-diamine complexes having the formula: ##STR20##wherein R₁ and R₂ independently of each other may be selected from thegroup consisting of hydrogen, an alkyl group having 1-20 carbon atoms, acycloalkyl group having from 3-7 carbon atoms in the ring, an aralkylgroup, and an aryl group having 1-20 carbon atoms, whereas R₁ and R₂together may form a cycloalkyl group having 3-7 carbon atoms in the ringand having the formula: ##STR21## wherein n is 2 to 7 and wherein R₃ andR₄ independently of each other are selected from the group consisting ofhydrogen, an alkyl group having 1-20 carbon atoms, an aryl group or anaralkyl group having 1-20 carbon atoms in the alkyl group and X is ananionic group, providing that when X is either chlorine or malonato, R₁,R₂, R₃ and R₄ are not each H; when X is chlorine and R₁ and R₂ are eachH, R₃ and R₄ are not each methyl; when X is chlorine and R₁ and R₂ areeach methyl; R₃ and R₄ are not each H, and when X is chlorine R₁ ishydrogen and R₂ is methyl, R₃ and R₄ are not each hydrogen. 2.Platinum-diamine complexes having the formula: ##STR22## wherein R₃ andR₄ independently of each other are selected from the group consisting ofhydrogen, alkyl group having 1-20 carbon atoms, an aryl group or anaralkyl group having 1-20 carbon atoms in the alkyl group and X is ananionic group, selected from the group consisting of chlorine, bromine,iodine, sulphate, phthalate, acetate, oxalate, malonate, substitutedmalonate, carboxylate, and isocitrate. 3.Cis-dichloro-1,1-di(aminomethyl)cycloalkyl platinum(II) having theformula: ##STR23## wherein n is 3 to
 7. 4.Cis-diiodo-1,1-di(aminomethyl)cyclohexane platinum(II) having theformula: ##STR24##
 5. Cis-cyclopentamethylenemalonato-1,1-di(aminomethyl)cyclohexane platinum(II) having the formula:##STR25##
 6. Cis-dichloro-(2-methyl-2-ethyl)-1,3-propane diamineplatinum(II) having the formula: ##STR26## 7.Cis-dichloro-2,2-diethyl-1,3-propane diamine platinum(II) having theformula: ##STR27##
 8. Cis-dichloro-1,1-di(aminomethyl)cyclopentaneplatinum(II) having the formula: ##STR28## 9.Cis-1,1-di(aminomethyl)cyclohexane platinum(II) sulphate having theformula: ##STR29##
 10. Cis-dichloro-1,1-di(aminomethyl)cyclobutaneplatinum(II) having the formula: ##STR30## 11.Cis-dichloro-2,2-dibenzyl-1,3-propane diamine platinum(II) having theformula: ##STR31##
 12. Cis-dichloro-2,2-diisopropyl-1,3-propane diamineplatinum(II) having the formula: ##STR32## 13.Cis-4-carboxyphtalato-1,1-di(aminomethyl)cyclohexane platinum(II) havingthe formula: ##STR33## 14.Cis-1,1-di(aminomethyl)-cyclohexane-bis(chloroacetato) platinum(II)having the formula: ##STR34##
 15. Cis-2,2-diethyl-1,3-propanediamineplatinum(II) sulphate having the formula: ##STR35## 16.Cis-1,1-di(aminomethyl)cyclohexanemalonato platinum(II) having theformula: ##STR36##
 17. Cis-1,1-di(aminomethyl)cyclohexanehydroxymalonatoplatinum(II) having the formula: ##STR37## 18.Cis-2,2-diethyl-1,3-diaminopropane 2-ethylmalonato platinum(II) havingthe formula: ##STR38##
 19. Cis-2,2-diethyl-1,3-diaminopropane2-hydroxymalonato platinum(II) having the formula: ##STR39## 20.Cis-1,1-di(aminomethyl)cyclhexane 2-ethylmalonato platinum(II) havingthe formula: ##STR40##
 21. Cis-2,2-diethyl-1,3-diaminopropane2-hydroxymalonato platinum(II) sodium salt, having the formula:##STR41##
 22. Cis-1,1-di(aminomethyl)cyclohexane1,1-cyclobutanedicarboxylato platinum(II) having the formula: ##STR42##23. Cis-2,2-diethyl-1,3-diaminopropane 1,1-cyclobutanedicarboxylatoplatinum(II) having the formula: ##STR43## 24.Cis-1,1-di(aminomethyl)cyclohexane platinum(II) isocitrate having theformula: ##STR44##
 25. Cis-dichloro-1,1-di(aminomethyl)cyclohexaneplatinum(II) having the formula: ##STR45##
 26. A pharmaceuticalcomposition comprising a liquid or solid carrier and an amount of atleast one of the compounds described in claim 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25sufficient to treat malignant tumors in mice.
 27. A method of treatingmalignant tumors in mice which consists of administering atherapuetically effective amount of the composition described in claim1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24 or 25 to mice having malignant tumors.
 28. Apharmaceutical composition comprising a liquid or solid carrier and anamount sufficient to treat malignant tumors in mice of at least one of aplatinum diamine complex having the formula: ##STR46## wherein R₁ and R₂independently of each other may be selected from the group consisting ofhydrogen, an alkyl group having 1-20 carbon atoms, a cycloalkyl grouphaving from 3-7 carbon atoms in the ring, an aralkyl group and an arylgroup having 1-20 carbon atoms, whereas R₁ and R₂ together may form acycloalkyl group having 3-7 carbon atoms in the ring and having theformula: ##STR47## wherein n is 2 to 7 and wherein R₃ and R₄independently of each other are selected from the group consisting ofhydrogen, an alkyl group having 1-20 carbon atoms, an aryl group or anaralkyl group having 1-20 carbon atoms in the alkyl group and X is ananionic group.
 29. A method of treating malignant tumors in mice whichconsists of administering a therapeutically effective amount of thecomposition described in claim 28 to mice having malignant tumors.